Benzylsulfonyl dipeptide derivatives such as for example benzylsulfonyl-D-Ser-L-homoPhe-(4-amidino-benzylamide) have previously been described as potent urokinase inhibitors (WO2009/026949). Urokinase (uPA), also called urokinase-type plasminogen activator, is a multidomain serine protease (EC 3.4.21.31). uPA is a 411 amino acid residue protein consisting of three domains: the growth factor-like domain (aa 4-43), the kringle domain (aa 47-135) and the catalytic “B” chain (amino acids 144-411) The kringle domain appears to bind heparin. The growth factor-like domain bears some similarity to the structure of epidermal growth factor (EGF), and is thus referred to as an EGF-like domain. uPA is synthesized as a zymogen (pro-uPA or single chain uPA), and is activated by proteolytic cleavage by plasmin between Lys158 and Ile159. The two resulting chains are kept together by a disulphide bond.
A principal substrate for uPA is plasminogen which is converted by cell surface bound uPA to plasmin. uPA is highly specific to a single peptide linkage in plasminogen. Activated plasmin degrades components of the extracellular matrix (fibrin, fibronectin, laminin, and proteoglycans) and also activates matrix metalloproteases (MMPs) thus promoting the degradation of collagen. Therefore, cosmetic composition which provide benzylsulfonyl-D-Ser-L-hPhe-4-amidinobenzylamide, provide a potent selective inhibitor of the urokinase, and a potent plasmin inhibitor while not inhibiting serine proteases, including kallikrein 5, kallikrein 7, elastase, factor VII, factor X and tissue-type plasminogen activator (tPA).
Thus, benzylsulfonyl dipeptide derivatives and in particular benzylsulfonyl-Ser-hPhe-4-amidinobenzylamide, (formula (II)) are important and valuable compounds for the use in the field of personal care application.

When a compound according to formula (I) is manufactured according to procedures as described in WO 2001/096286, WO 2003/076391, or as published by A. Schweinitz et al. in JBC 2004, Vol 279 (32), p 33613-3622, the yield of the resulting product is very limited because of the surprisingly low solubility of said compounds of formula (I), thereby drastically increasing the cost of production of said compounds. The poor yield of the process of the prior art is demonstrated in comparative examples. Furthermore; the above described processes of the prior art include an ionic exchange chromatographic step which is not convenient for industrial scale production with poorly soluble compounds.
Therefore the goal of the present invention was to find an improved process for coupling an amino acid derivative of formula (III), herein designated as benzylsulfonyl-Ser (tBu)-OH with a compound of formula (IV) herein designated as X-4-amidinobenzylamide thereby leading to the compound of formula (I) with an excellent yield, a minimal amount of side products, fewer steps than the processes of the prior art, thereby leading to a significant reduction of the manufacturing cost.
wherein R is a C1 to C6 linear or branched aliphatic hydrocarbon chain optionally substituted with a C6 to C10 aromatic group.